Background: There is some evidence that propofol may reduce post-operative pain. However, the results on the analgesic effects of propofol are inconsistent. Thus, we hypothesized that propofol reduces acute pain if confounding factors like opioids are avoided. Methods: In this prospective, randomized, subject-and assessor-blind, parallel-group, head-to-head comparative study, 90 American Society of Anesthesiologists I or II females underwent elective laparoscopies were randomized to receive either propofol-based (PR), or sevoflurane-based (SR), or sevofluranepropofol- based anesthesia (SPR). Pain score at rest assessed by a numerical rating scale at 0.5 h after surgery was the primary outcome. The secondary outcomes included pain score at 1 and 24 h post-operatively, duration of post-anesthesia care units stay (PACU), incidence of post-operative nausea and vomiting, incidence of shivering, and post-operative quality of recovery score (QoR-40) within the first 24 h post-operatively. Results: No patients received rescue analgesia. The pain score at 0.5 h post-operatively was less in group PR when compared with group SR (0.7 +/- 1.4 vs. 2.1 +/- 1.8; P = 0.010) or group SPR (0.7 +/- 1.4 vs. 2.1 +/- 2.2; P = 0.008). Group PR was also associated with shorter PACU stay than group SR (21.8 +/- 5.7 vs. 26.2 +/- 6.9; P = 0.050) or group SPR (21.8 +/- 5.7 vs. 27.8 +/- 8.9; P = 0.005). Intraoperative bispectral index values, hemodynamic values and post-operative QoR-40 scores did not differ among the three groups. Conclusions: Propofol anesthesia was associated with significantly less pain at 0.5 and 1 h after surgery in patients undergoing gynecological laparoscopies with planned opioid-free post-operative analgesia.